Lysosomal alterations in heart and liver of mice treated with doxorubicin

Gebbia, Nicola; Leto, Gaetano; Gagliano, M.; Tumminello, Francesca Maria; Rausa, L

doi:10.1007/bf00257289

Cited by 20 publications

(9 citation statements)

References 14 publications

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“…In fact, an early literature reported lysosome changes in cardiomyocytes, in terms of both numbers and morphology, induced by doxorubicin 1, 49 . It has been reported that doxorubicin also increases lysosomal membrane leakage 50 , although the changes seemed to be modest. Our data, for the first time, show that doxorubicin perturbs lysosomal function via inhibition of its luminal acidity.…”

Section: Discussionmentioning

confidence: 84%

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

et al. 2016

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Background The clinical use of doxorubicin is limited by cardiotoxicity. Histopathologic changes include interstitial myocardial fibrosis and appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Methods and Results Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity due to haploinsufficiency for Beclin 1. Beclin 1+/− mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals over-expressing Beclin 1 manifested an amplified cardiotoxic response. Conclusions Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.

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Section: Discussionmentioning

confidence: 84%

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

et al. 2016

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“…A further paper gives supplementary information on the phenomena to be observed in aminoglycoside nephropathy of lysosomal origin (Roels et al 1984). The publication of Gebbia et al (1985) reports the effect of doxorubicin on the lysosomes of the heart and liver. One of the most recent substance-relevant publications is concerned with the effect of carcinogenic drugs on lysosomes (Bradley et al 1987).…”

Section: Discussionmentioning

confidence: 99%

Drug-induced lysosomal disorders in laboratory animals: new substances acting on lysosomes

Schneider¹

1992

Arch Toxicol

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Several substances with lysosomotropic activity were investigated in toxicological studies. AR-L 115 BS (sulmazol, a cardiotonic agent) was tested on beagle dogs; HX-CH 44 BS (a beta-blocker) and SX-AB 1316 SE (an antithrombotic agent) were tested on rats, and AF-CX 1325 XX (an antiepileptic agent) was tested on both rats and beagle dogs. All organ systems were examined morphologically by light and/or electron microscopy. When an increase in the number of lysosomes occurred this was confirmed by the pigment scheme according to Krutsay (1971) as well as by the detection of acid phosphatase and compared with earlier histochemical results. At higher dosages, all substances caused very marked proliferation of lysosomes in the liver and/or kidneys. HX-CH 44 BS also caused such proliferation in striated muscles and in the lungs. A brown discolouration of the kidneys was found with sulmazol and AF-CX 1325 XX. This finding corresponded to the microscopically detectable occurrence of numerous lipofuscin granules. The reticulum cells in the lymph nodes of dogs were also affected by AF-CX 1325 XX. It is concluded that the proliferation of lysosomes in various organs after administration of the above-mentioned substances is due to an excess of substance. The increased substance in the body is then stored in the lysosomes. With HX-CH 44 BS, lysosomal autodigestion of mitochondria in the skeletal musculature and in the alveolar macrophages of the lungs was found. The selective lysosomal incorporation of mitochondria has not been described up to now and in our opinion, this constitutes a special feature. The results otherwise largely correspond to those already described in the literature. Systemic phospholipidosis such as occurs with some other substances was not detectable. The incorporation of the substance causes several types of lysosomal inclusion. Uptake of the substance in lysosomes either leads to overt autodigestion of organelles such as mitochondria (HX-CH 44 BS) or peroxisomes or to residual lysosomes of dense structure which histochemically resemble lipofuscin. SX-AB 1316 SE serves as an example of a substance which is stored directly by lysosomes in crystalline form. Above all, in the liver the substance is taken up not only by the sinusoidal stellate cells but also by hepatocytes.

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“…After long-term ADR treatment in mice, changes in lysosomal enzyme activity have been reported for cathepsin D in the heart, and to a lesser extent in the liver [27]. In vitro stud ies revealed a certain accumulation o f ADR in the lysosomal compartment o f fibroblasts [28].…”

Section: Discussionmentioning

confidence: 99%

Cathepsin B and L in Isolated Proximal Tubular Segments during Acute and Chronic Proteinuria

Eisenberger¹,

Fels²,

Olbricht³

et al. 1995

Kidney Blood Press Res

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Acute and chronic proteinuria were studied in rats, using lysosomal cathepsin B and L as marker enzymes for tubular protein degradation. The activity of cathepsin B and L has been determined in microdissected segments S1, S2 and S3 of the proximal tubule by an ultramicroassay. Z-Phenylalanyl-arginine-7-amido-4-methylcoumarin served as a substrate. In normoproteinuric Sprague-Dawley rats, induction of acute unselective glomerular proteinuria with Adriamycin (5 mg/kg body weight) revealed a moderate activity increase of cathepsin B and L in the S2 segment, reaching 12.6 ± 5.6 versus 8.6 ± 4.2 pmol·mm^-1·min^-1 in controls. In contrast, Munich Wistar Frömter (MWF) rats, that are characterized by a genetically determined, chronically elevated glomerular protein excretion, showed a very high activity of cathepsin selectively in S2 of 25.0+12.1 pmol· mm^-1 min^-1. Acute proteinuria induced by Adriamycin in chronic proteinuric MWF rats could increase cathepsin activity in the S3 segment only, showing 12.0 ± 8.3 versus 6.8 ± 4.0 pmol-mm^-1 min^-1 in MWF control rats. In conclusion, chronically increased protein filtration changes the functional reserve capacity of the proximal tubule. While acutely induced glomerular proteinuria in normoproteinuric rats stimulates lysosomal proteolytic activity mainly in S2 segment, chronic proteinuric MWF rats may display already a maximally stimulated cathepsin activity in this segment probably due to long-term increased tubular protein load. In case of acute elevation of chronic proteinuria, the consecutive S3 segment shows increased lysosomal function for protein conservation.

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Lysosomal alterations in heart and liver of mice treated with doxorubicin

Cited by 20 publications

References 14 publications

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Drug-induced lysosomal disorders in laboratory animals: new substances acting on lysosomes

Cathepsin B and L in Isolated Proximal Tubular Segments during Acute and Chronic Proteinuria

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